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Current Neuropharmacology, 2017, 15, 184-194 184 Send Orders for Reprints to [email protected] Current Neuropharmacology, 2017, 15, 184-194 REVIEW ARTICLE ISSN: 1570-159X eISSN: 1875-6190 Impact Common Neurogenetic Diagnosis and Meso-Limbic Manipulation of Factor: 3.753 Hypodopaminergic Function in Reward Deficiency Syndrome (RDS): Changing the Recovery Landscape BENTHAM SCIENCE Kenneth Blum1-6,8,11,12,14,*, Marcelo Febo1, Rajendra D. Badgaiyan7, Zsolt Demetrovics8, Thomas Simpatico2, Claudia Fahlke9, Oscar-Berman M10, Mona Li11, Kristina Dushaj11 12,13 and Mark S. Gold 1Department of Psychiatry, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL, USA; 2Department of Psychiatry, University of Vermont, Burlington, VT, USA; 3 Division of Neuroscience Based Therapy, Summit Estates Recovery Center, Las Gatos, CA, USA; 4Dominion Diagnostics, LLC, North Kingstown, RI, USA; 5IGENE, LLC, Austin, TX, USA; 6Department of Nutrigenomics, RDSolutions, Inc., Salt Lake City, UT, USA; 7Division of Neuroimaging, Department of Psychiatry, University of Minnesota College of Medicine, Minneapolis, MN, USA; 8Department of Psychology, Eotvos Lorand University, Budapest, Hungary; 9Department of Psychology, University of Gothenburg, Göteborg, Sweden; 10Departments of Psychiatry and Anatomy & Neurobiology, Boston University School of Medicine and Boston VA Healthcare System, Boston, MA, USA; 11PATH Foundation NY, New York, NY, USA; 12Departments of Psychiatry & Behavioral Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA; 13Department of Psychiatry, Washington University School of Medicine. St. Louis, MO, USA; 14Division of Neuroscience Research and Addiction Therapy, The Shores Treatment and Recovery, Port Saint Lucie, FL, USA Abstract: Background: In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed “Brain Reward Cascade.” These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed “Reward Deficiency Syndrome” (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. A R T I C L E H I S T O R Y Objective: In this review article, we attempt to clarify these terms and provide a Received: September 08, 2015 Revised: April 11, 2016 working model to accurately diagnose and treat these unwanted behaviors. Accepted: April 21, 2016 Method: We are hereby proposing the development of a translational model we term "Reward Deficiency DOI: 10.2174/1570159X13666160512150 Solution System™" that incorporates neurogenetic testing and meso-limbic manipulation of a 918 “hypodopaminergic” trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced “dopamine resistance,” while embracing “dopamine homeostasis.” Result: The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184. Keywords: Dopamine homeostasis, genetics, reward deficiency solution system, Reward Deficiency Syndrome (RDS). INTRODUCTION only to be a precursor to Norepinephrine, was indeed a neurotransmitter by itself having an important role in brain Nobel prize winners, Arvid Carlsson, Paul Greengard, function. Greengard received the Nobel Prize because he and Eric Kandel, supported initial studies on dopamine as a showed the role of Dopamine in the synapse and Kandel neurotransmitter playing a significant part in the Central received the Nobel Prize for his contribution to the role of Nervous system (CNS). Carlsson was rewarded for his seminal work in the 1950’s showing that dopamine, thought Dopamine in learning and memory [1]. The work of Carlsson lead to not only the successful treatment of Parkinson Disease, but depression and even *Address correspondence to this author at the Department of Psychiatry & McKnight Brain Institute, University of Florida, College of Medicine, Box Schizophrenia. However, it is accepted that by using the 100183 Gainesville, FL, USA 32610-0183; Tel: 352-392-6680; Fax: 352-392- strong dopamine D2 receptor agonist L-Dopa there are issues 8217; E-mail: [email protected] related to motor control and dyskinesia [2]. Moreover, the 1875-6190/17 $58.00+.00 ©2017 Bentham Science Publishers Current Neuropharmacology Common Neurogenetic Diagnosis and Meso-Limbic Manipulation Current Neuropharmacology, 2017, Vol. 15, No. 1 185 role of antidepressants involving transporter systems and brain neurotransmitter that regulates perception of welfare via inhibition of the catabolic enzymes Monoamine–Oxidase the balancing of D1/D2 receptors [17, 18]. The combination (MOA-A,B) and Catecholamine-Methyl-Transferase (COMT) of dopamine as well as additional neurotransmitters like for depression is fraught with many issues related to side serotonin, neuropeptides, and other dominant brain enzymes effects and even mood alterations [3]. Finally, the utilization is responsible for producing this sense of well being. For of an anti-psychotic agent like Haloperidol that block example, decreased levels of serotonin are connected to dopamines response at D2 receptors could result in severe episodes of depression. mood changes as well and they have significant side effects Opioids in the reward circuitry of the brain are [4]. With due respect of these important findings still particularly connected to feelings of well being [19]. The important in today’s medical arsenal against these intrusive multiplex of such neurotransmitters are produced in the brain brain disorders, we can improve on these important medicaments. Interestingly, prior to 1968, little was known and so are their receptors through transcription process involving mRNA [20]. We are cognizant that there are many about the role of Dopamine and for example, ethanol abuse, associations of non-coding microRNAs (miRNAs) in all intoxication and clinically induced alcoholism. However, addictions. following the development of the Institutes of both drug abuse (National Institute of Drug Abuse) and alcoholism It is known that miRNAs are small non-coding RNAs (National Institute of Alcohol Abuse & Alcoholism) by the that function as translational repressors and represent an National Institutes of Health, the understanding of how these important element in cellular development as well as mental diverse addictive substances (e.g. glucose, alcohol, cocaine, illness. MicroRNA sequences and their target sites in heroin, nicotine, etc.) pharmacologically act, especially in miRNAs reveal a degree of commonality across species. the CNS and their commonality of neuro-functionality across It has now been adequately researched and found that a mental illness has been a wonderful work in progress [5]. single miRNA can recognize the 3'untranslated region of miRNAs in a sequence- specific manner to repress the Since the 1960’s and 70’s, the role of Dopamine was beginning to entice scientists and it was not until 1969 that protein expression of hundreds of targeted miRNAs. Most importantly, the human genome encodes more than 1000 the very first Neuroscience Society meeting occurred, miRNAs which effects over 60% of mammalian and human consisting of less than 100 members. In fact, Blum [6] was transcripts. Current data proposes that miRNAs control the first to show the role of dopamine at the neuromuscular expression of mu opiate receptors and in fact it is known that junction revealing that tremors could occur as a motor an opiate agonist like morphine and fentanyl can alter response to dopamine. This had relevance to the role of dopamine in Parkinsonism. Other work by Blum et al. [7-9] specific miRNAs signaling as well. The interaction between specific miRNAs and opiates and their respective receptors revealed that dopamine played an important role in will impact not only cell development, but analgesia, pain alcohol withdrawal symptomatology similar to morphine tolerance, and addiction [21]. He and Wang [22] suggested withdrawal. This served, along with the seminal work of that the let- 7 family of miRNAs is a critical regulator of mu Davis and Walsh [10], as the basis of common mechanisms. opiate receptor function in opioid tolerance. In 1977, Blum edited a book “Alcohol & Opiates” devoted to common mechanisms between these two seemingly Most et al. [23] has suggested that miRNA manipulation diverse chemical structures [11]. Melchoir and Myers in the may cause cocaine-seeking behavior, reward processing of mid 70’s also showed genetic differences in ethanol drinking cocaine, and self-administration rates of alcohol – all of various rat strains utilizing methods to destroy addiction-related behaviors. It has been adequately shown that serotonergic and dopaminergic pathways [12]. Following miR-212 causes a level of susceptibility in cocaine addiction. these earlier studies, Dackis & Gold developed the concept This is supported by a number of findings: of the “dopamine depletion hypothesis” specific for cocaine addiction [13]. Over a five-year period, there has been a 1) Compulsive cocaine-related behaviors are caused by plethora of research devoted to the role of neurotransmitters increased miR-212 manifestation within the rat dorsal and brain function [14]. During this time, Blum & striatum; 2) increased
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